Peptide chemical ligation chemistries, which allow the chemoselective coupling of unprotected peptide fragments, are useful tools for synthesizing native polypeptides or unnatural peptide-based macromolecules. We show here that the phenylthiocarbonyl group can be easily introduced into peptides on alpha or epsilon amino groups using phenylthiochloroformate and standard solid-phase method. It reacts chemoselectively with cysteinyl peptides to give an alkylthiocarbamate bond. S,N-shift of the alkylaminocarbonyl group from the Cys side chain to the alpha-amino group did not occur. The method was used for linking two peptide chains through their N-termini, for the synthesis of a cyclic peptide or for the synthesis of di- or tetravalent multiple antigenic peptides (MAPs). Thiocarbamate ligation is thus complementary to thioether, thioester or disulfide ligation methods.
Glycine is a amino acid frequently found in peptides. Substitution of a glycine residue by an azaglycine allows the modulation of peptide conformation, bioactivity, or stability. Azapeptides are usually prepared using solid-phase synthetic procedures. We show here that azaGly peptides can be assembled chemoselectively and without racemization using unprotected peptide fragments by silver-catalyzed reaction of C-terminal peptide hydrazides with N-terminal phenylthiocarbonyl peptides. The reaction was performed in a tBuOH/water mixture and the control of apparent pH permitted the clean formation of the azaGly bond in the presence of lysine residues. We show also that this novel ligation method, called azaGly ligation, can be used for the assembly of lipopeptides. For this, lipid hydrazides were reacted with a phenylthiocarbonyl peptide in the presence of silver ions. This ligation method allows incorporation of acid-sensitive lipid moieties that are incompatible with standard solid-phase peptide synthesis procedures, and more generally should be of interest for the modification of peptides by sensitive acyl moieties.
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